Journal
NATURE GENETICS
Volume 45, Issue 8, Pages 947-U152Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2670
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Funding
- NIHR Exeter Clinical Research Facility
- Wellcome Trust [098395/Z/12/A, 098395/Z/12/Z, 098498/Z/12/Z]
- Diabetes UK
- UK NIHR Cambridge Biomedical Research Centre
- Agency for Science, Technology and Research, Singapore (A*STAR)
- National Cancer Institute of the US National Institutes of Health [R01CA102029, P01CA077852]
- MRC [G0600717] Funding Source: UKRI
- Diabetes UK [11/0004316] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5/B, G0600717, G0600717B] Funding Source: researchfish
- National Institute for Health Research [ACF-2007-23-001, NF-SI-0611-10219] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [R01CA102029, P01CA077852] Funding Source: NIH RePORTER
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DNA polymerase delta, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication(1). It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers(2). Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.
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